Park Chulhun, Zuo Jieyu, Gil Myung-Chul, Löbenberg Raimar, Lee Beom-Jin
College of Pharmacy, Jeju National University, Jeju 63243, Republic of Korea.
Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada.
Pharmaceutics. 2023 Oct 26;15(11):2533. doi: 10.3390/pharmaceutics15112533.
This study aimed to investigate the enhancement of cannabinoid acid solubility and stability through the formation of a cannabinoid acid/cyclodextrin (CD) inclusion complex. Two cannabinoid acids, tetrahydro-cannabinolic acid (THCA) and cannabidiolic acid (CBDA), were selected as a model drug along with five types of CD: α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD), and methylated-β-cyclodextrin (M-β-CD). Phase solubility studies were conducted using various types of CD to determine the complex stoichiometry. The preparation methods of the CD inclusion complex were optimized by adjusting the loading pH solution and the drying processes (spray-drying, freeze-drying, spray-freeze-drying). The drying process of the cannabinoid acid/M-β-CD inclusion complex was further optimized through the spray-freeze-drying method. These CD complexes were characterized using solubility determination, differential scanning calorimetry (DSC), field-emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), and H NMR spectroscopy. DSC, XRD, and FE-SEM studies confirmed the non-crystalline state of the cannabinoid acid/CD inclusion complex. The permeation of THCA or CBDA from the M-β-CD spray-freeze-dried inclusion complex was highly improved compared to those of cannabis ethanolic extracts under simulated physiological conditions. The stability of the cannabinoid acid/M-β-CD inclusion complex was maintained for 7 days in a simulated physiological condition. Furthermore, the minimum inhibitory concentration of cannabinoid acid/M-β-CD inclusion complex had superior anti-cancer activity in MCF-7 breast cancer cell lines compared to cannabinoid acid alone. The improved physicochemical and biological performances indicated that these CD inclusion complexes could provide a promising option for loading lipophilic cannabinoids in cannabis-derived drug products.
本研究旨在通过形成大麻素酸/环糊精（CD）包合物来研究提高大麻素酸的溶解度和稳定性。选择两种大麻素酸，四氢大麻酚酸（THCA）和大麻二酚酸（CBDA）作为模型药物，同时选择五种类型的CD：α-环糊精（α-CD）、β-环糊精（β-CD）、γ-环糊精（γ-CD）、羟丙基-β-环糊精（HP-β-CD）和甲基化-β-环糊精（M-β-CD）。使用各种类型的CD进行相溶解度研究，以确定络合物化学计量比。通过调整负载pH溶液和干燥工艺（喷雾干燥、冷冻干燥、喷雾冷冻干燥）优化CD包合物的制备方法。通过喷雾冷冻干燥法进一步优化大麻素酸/M-β-CD包合物的干燥工艺。使用溶解度测定、差示扫描量热法（DSC）、场发射扫描电子显微镜（FE-SEM）、X射线衍射（XRD）和1H NMR光谱对这些CD络合物进行表征。DSC、XRD和FE-SEM研究证实了大麻素酸/CD包合物的非晶态。在模拟生理条件下，与大麻乙醇提取物相比，M-β-CD喷雾冷冻干燥包合物中THCA或CBDA的渗透率有显著提高。大麻素酸/M-β-CD包合物在模拟生理条件下可保持7天的稳定性。此外，与单独的大麻素酸相比，大麻素酸/M-β-CD包合物的最低抑菌浓度在MCF-7乳腺癌细胞系中具有更强的抗癌活性。理化和生物学性能的改善表明，这些CD包合物可为大麻衍生药物产品中亲脂性大麻素的负载提供一个有前景的选择。
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